14-32824025-T-C

Variant names:

• chr14-32824025-T-C
• rs1293959722
• NM_004274.5:c.6212T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004274.5(AKAP6):​c.6212T>C​(p.Leu2071Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AKAP6 NM_004274.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05

Genes affected

AKAP6 (HGNC:376): (A-kinase anchoring protein 6) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP6	NM_004274.5	c.6212T>C	p.Leu2071Pro	missense_variant	Exon 13 of 14	ENST00000280979.9	NP_004265.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP6	ENST00000280979.9	c.6212T>C	p.Leu2071Pro	missense_variant	Exon 13 of 14	1	NM_004274.5	ENSP00000280979.4
AKAP6	ENST00000557272.1	c.3589-5823T>C		intron_variant	Intron 12 of 12	5		ENSP00000451247.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461606 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.00020	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.86
MVP		0.88
MPC		0.46
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.67
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1293959722; hg19: chr14-33293231;